Benzopyran derivatives

ABSTRACT

The invention relates to benzopyran compounds of formula (I) possessing pharmacological activity, as well as to pharmaceutical compositions containing the compounds of formula (I) and processes for the preparation thereof. ##STR1##

This application is a 371 of PCT/HU93/00079 filed Dec. 20, 1993.

This application is a 371 of PCT/HU93/00079 filed Dec. 20, 1993.

FIELD OF THE INVENTION

The present invention relates to novel benzopyran derivatives of theformula ##STR2## possessing pharmacological activity, as well as topharmaceutical compositions containing the compounds of the formula (I).Further, the present invention relates to methods for preparing .thesecompounds and the pharmaceutical compositions containing these compoundsas well as novel intermediates.

BACKGROUND OF THE INVENTION

The preparation of certain compounds of the formula (I) havinghypotensive effect by activating the potassium canal andpharmaceutically acceptable acid addition salts thereof is disclosed inEuropean patent specifications Nos. 0,076,075, 0,093,535, 0,120,426,0,120,427, 0,120,428, 0126,311 and 0,126,350. In the formula (I)

R₁ stands for a (C₁₋₄ alkyl)carbonyl, (C₁₋₄ alkoxy)carbonyl, nitro,formyl or cyano group or a halo atom,

R₂ stands for a hydrogen atom,

R₃ stands for a hydrogen atom or a C₁₋₄ alkyl group,

R₄ stands for a C₁₋₄ alkyl group and

the lactame ring is in trans position related to the hydroxy group.

The preparation of the compounds as disclosed in the literature isillustrated by reaction scheme No. 1: ##STR3## comprising reacting asuitably substituted phenol of the formula (II) with 3-chloro-1-propyneof the formula (III) resulting in an arylpropargyl ether of the formula(IV), a chromene of the formula (V) is then formed from the ether bythermic cyclization. Thereafter 3-bromo-4-chromanol of the formula (VII)may be formed from the chromene of the formula (V) either in one step byadding hypobromic acid, or in two steps, by hydrolyzing in aqueousacetone 3,4-dibromochromane of the formula (VI) obtained by addingelemental bromine to chromene of the formula (V). 3-Bromo-4-chromanol isconverted into a 3,4-epoxy derivative of the formula (VIII) in analkaline medium, compounds of the formula (I) are then prepared in aspecific reaction.

The symbols in reaction scheme i stand for the following reactionconditions:

a: room temperature, a 40% sodium hydroxide solution, benzyl trimethylammonium hydroxide and methanol;

b: boiling under reflux in ortho dichlorobenzene;

c: N-bromosuccinimide, water and dimethyl sulfoxide;

d: bromine and carbon tetrachloride;

e: acetone and water;

f: sodium hydroxide, water and dioxane;

g: 2-pyrrolidone, sodium hydride and dimethyl sulfoxide.

If R₂ does not stand for hydrogen in the process described above, twosubstances are formed in reaction b as the ring formation may occur attwo places. The formed disadvantageous regioisomer of the formula (Va)has to be separated from the reaction mixture which process iscomplicated and decreases the total yield.

In European patent specification No. 0,277,611 the preparation of suchbenzopyran derivatives of the formula (I) is disclosed in which

R₁ stands for an arylsulfonyl or methylsulfonyl group,

R₂ stands for a hydrogen atom, a hydroxy or C₁₋₂ alkoxy group,

R₃ is a hydrogen atom or a C₁₋₄ alkyl group,

R₄ is a C₁₋₄ alkyl group and

the lactame ring is in trans position related to the hydroxy group.

In the electrophilic substitution of 4-chromanone of the formula##STR4## wherein R₂ stands for C₁₋₄ alkoxy, R₃ and R₄ stand for C₁₋₄alkyl, a 4-chromanone of the formula ##STR5## is obtained, the latterbeing reduced to 4- chromanol of the formula ##STR6## in a furtherreaction to obtain a chromene of the formula (V) in a water eliminatingreaction. The derivative of the formula (I) is obtained from thiscompound through compounds of the formula (VII), then (VIII).

In the formulae

R₁ stands for an arylsulfonyl or methylsulfonyl group,

R₂ stands for a hydrogen atom, hydroxy or C₁₋₂ alkoxy,

R₃ is a hydrogen atom or a C₁₋₄ alkyl group and

R₄ is a C₁₋₄ alkyl group and

the lactame ring is in trans position related to the hydroxy group.

No process is known at the same time for the preparation of thecompounds of the formula (I), wherein

R₁ stands for a C₁₋₆ alkyloxy, alkenyloxy, alkynyloxy, cycloalkoxy,aryloxy, aralkoxy, hydroxy, nitro, cyano, formyl, C₁₋₆ acyl orcyano-C₁₋₆ -alkyl group or halo,

R₂ stands for a C₁₋₆ alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy,aryloxy, aralkoxy or hydroxy group, or

R₁ and R₂ stand together for alkylenedioxy, and

R₃ and R₄ stand together for a C₁₋₆ alkyl group,

The above compounds of the formula are novel.

According to literature data (J. Med. Chem. 1990, 33, 492) in compoundsof the formula (I) for reaching hypotensive effect R₁ should represent astrong electron withdrawing substituent and R₂ generally a hydrogenatom.

We have, however, found that compounds of the formula (I) according theinvention also possess a hypotensive effect. These compounds arecharacterized by being substituted together in positions 6 and 7,further, R₁ is not necessarily a strong electron withdrawing substituentand R₂ is not a hydrogen atom.

Further, we have found that benzopyrans of the formula (I) according toour invention also exert their effect by activating the potassium canal.Thus, these compounds may be useful according to David W. Robertson etal in the following fields of the therapy: a) hypertension; b) asthma;c) diseases of the urinary organs; d) heart failure, g) diseases of thecentral nervous system; and f) paralysis.

The invention provides processes for preparing the new compounds of theformula (I) through intermediates, the dominant part of which are alsonovel.

According to the invention compounds of the formula (I), wherein

R₁ stands for a C₁₋₆ alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy,aryloxy, aralkoxy, hydroxy, nitro, cyano, formyl, C₁₋₆ acyl orcyano-C₁₋₆ -alkyl group or halo,

R₂ stands for a C₁₋₆ alkoxy, cycloalkoxy, aryloxy, aralkoxy group, or

R₁ and R₂ together stand for alkylenedioxy, and

R₃ and R₄ stand for a C₁₋₆ alkyl group, with the provision that if R₁ iscyano or nitro, then R₂ cannot stand for methoxy or ethoxy, may beprepared by reducing a 4-chromanone of the formula (XVIII), wherein

R₁ stands for a C₁₋₆ alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy,aryloxy, aralkoxy, hydroxy, nitro, cyano, formyl, C₁₋₆ acyl orcyano-C₁₋₆ -alkyl group or halo,

R₂ stands for a C₁₋₆ alkoxy, cycloalkoxy, aryloxy, aralkoxy group,

R₁ and R₂ together stand for alkylenedioxy, and

R₃ and R₄ stand for a C₁₋₆ alkyl group,

with metal hydrides, preferably sodium tetrahydroborate, in an amount of1-5 equivalents, preferably 1.1 equivalents, in a polar or apolarsolvent, preferably methanol and/or benzene, at a temperature of 0° to100° C., preferably at 25° C., into a 4-chromanol derivative of theformula (XIX), boiling said 4-chromanol derivative of the formula (XIX)in a water immiscible solvent forming with it an azeotropic mixture,preferably in benzene, in the presence of a catalytic amount ofp-toluene sulfonic acid for the preparation of 2H-chromene of theformula (V), converting said 2H-chromene of the formula (V) into abromohydrine of the formula (VII) with N-bromosuccinimide in a dipolaraprotic solvent containing water as well, preferably in dimethylsulfoxide, at a temperature of -10° to 50° C., preferably at 15° C.,then reacting said bromohydrine derivative of the formula (VII) with2-pyrrolidone in the presence of alkali metal alcoholates, preferablypotassium tert-butoxide, at a temperature of 0° to 100° C., preferablyat 25° C.

Compounds of the formula (I), wherein

R₁ stands for a C₁₋₆ alkoxy, cycloalkoxy, aryloxy, aralkoxy, hydroxy,nitro, cyano, formyl, C₁₋₆ acyl or cyano-C₁₋₆ -alkyl group or halo,

R₂ stands for a hydroxy group and

R₃ and R₄ stand for a C₁₋₆ alkyl group,

may be prepared hydrogenating compounds of the formula (I), wherein

R₁ stands for a C₁₋₆ alkoxy, cycloalkoxy, aryloxy, aralkoxy, hydroxy,nitro, cyano, formyl, C₁₋₆ acyl or cyano-C₁₋₆ -alkyl group or a haloatom,

R₂ stands for an aralkoxy, preferably benzyloxy group and

R₃ and R₄ stand for a C₁₋₆ alkyl group,

in a polar protic solvent, preferably methanol, in the presence of acatalyst, preferably palladium-on-charcoal catalyst, at a hydrogenpressure of 1 to 10 bar, preferably 5 bar.

Compounds of the formula (I), wherein

R₁ stands for a C₁₋₆ alkoxy alkenyloxy, alkynyloxy, cycloalkoxy,aryloxy, aralkoxy, hydroxy, nitro, cyano, formyl, C₁₋₆ acyl orcyano-C₁₋₆ -alkyl group or halo,

R₂ stands for an alkenyloxy or alkynyloxy group and

R₃ and R₄ stand for a C₁₋₆ alkyl group,

may be prepared by reacting a compound of the formula (I), wherein

R₁ stands for a C₁₋₆ alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy,aryloxy, aralkoxy, hydroxy, nitro, cyano, formyl, C₁₋₆ acyl orcyano-C₁₋₆ alkyl group or halo,

R₂ stands for a hydroxy group and

R₃ and R₄ stand for a C₁₋₆ alkyl group,

with suitable alkenyl or alkynyl halogenides in a polar aprotic solvent,preferably acetone, in the presence of an acid binding agent, preferablypotassium carbonate, and a catalytic amount of potassium iodide.

The invention also relates to the novel process by which 4-chromanone ofthe formula (XVIII) is prepared. Thus

a) if in the formula (X) R₁ stands for a nitro group, R₂ is a C₁₋₄alkyloxy group, R₃ and R₄ stand together for a C₁₋₄ dialkyl group, thena compound of the formula ##STR7## is obtained by nitrating a compoundof the formula (IX), wherein R₂ is a C₁₋₄ alkoxy group, R₃ and R₄ standtogether for a C₁₋₄ alkyl group (reaction scheme No. 2). ##STR8##

The nitration is performed with copper(II)nitrate in carboxylicanhydride, preferably acetic anhydride, at a temperature of 20°-100° C.,preferably at 40° C. Compounds of the formula (X) are novel except whenR₂ is CH₃ O (see Panayiotis Anastasis and Philip E. Brown: J- Chem. Soc.Perkin Trans. I., p. 2013-2018, 1982).

b) If in the formula (XII) R₁ stands for a cyano group, R₂ stands for aC₃₋₄ alkoxy group, R₃ and R₄ together stand for a C₁₋₄ alkyl group, thena compound of the formula (XII) is prepared from a formyl derivative ofthe formula (XI) by boiling same in 100% formic acid in the presence ofhydroxylamine hydrochloric salt and alkali metal formiate. Said formylderivative of the formula (XI) is obtained by subjecting a compound ofthe formula (IX), wherein R₂ stand for a C₁₋₄ alkyloxy, R₃ and R₄ standtogether for a C₁₋₅ alkyl, to Vilsmeier formylation (reaction scheme 2).The preparation is performed by reacting a compound of the formula (IX),wherein R₂ stands for a C₃₋₄ alkoxy group and R₃ and R₄ together standfor a C₁₋₄ alkyl group, in a mixture of phosphorous trichloride oxideand dimethyl formamide at a temperature of 25°-100° C., preferably at80° C., to obtain a derivative of the formula (XI), dissolving saidcompound of the formula (XI) in carboxylic acid and boiling the mixturepreferably in formic acid, in the presence of an alkali metal formiate,preferably sodium formiate.

The compounds of the formula (XII) are novel.

c) If in the formula (XV) R₁ stands for a C₁₋₄ alkyl-cyano group, R₂stands for a C₁₋₄ alkoxy group, R₃ and R₄ together stand for a C₁₋₄alkyl group, then 4-chromanone of the formula (XV), wherein R₂ standsfor a C₁₋₄ alkoxy group, R₃ and R₄ together stand for a C₁₋₄ alkylgroup, is prepared as follows: a compound of the formula (XI) andacetonitrile are condensed to obtain a compound of the formula (XIII).This compound is converted into a compound of the formula (XIV) byadding water to obtain a compound of the formula (XV) by catalytichydrogenation (reaction scheme 2). The synthesis is carried out bycondensing a compound of the formula (XI),

wherein

R₂ stands for a C₁₋₄ alkoxy group and

R₃ and R₄ stand together for a C₁₋₄ alkyl group, with acetonitrile inthe presence of an alkali metal alcoholate, preferably potassiumtert-butoxide, at a temperature of 0° to 100° C., preferably at 25° C.,to obtain compounds of the formula (XIII), reacting said compounds ofthe formula (XIII) at a temperature of 0° to 100° C., preferably at 25°C. in the presence of a mineral acid, preferably 70% perchloric acid, toobtain a compound of the formula (XIV), then hydrogenating said compoundof the formula (XIV) in a polar protic solvent, preferably methanol, inthe presence of .a catalyst, preferably palladium-on-charcoal catalyst,at a hydrogen pressure of 1 to 10 bar, preferably at 5 bar. Compounds ofthe formula (XV) are novel.

d) If in general the formula (XVIII) R₁ stands for a hydrogen atom, R₂stands for a hydroxy group, R₃ and R₄ together stand for a C₂₋₆ alkylgroup, then 4-chromanone of the formula (XVIII) is obtained bycondensing resacetophenone of the formula ##STR9## and a dialkyl ketoneof the formula ##STR10## in which formulae R₃ and R₄ together stand fora C₂₋₆ alkyl group (reaction scheme 3). ##STR11##

The reaction is performed by reacting a resacetophenone of the formula(XVI) with dialkyl ketone of the formula (XVII), wherein R₃ and R₄ standfor C₂₋₆ alkyl, at a temperature of 0° to 100° C., preferably at 25° C.,in the presence of a cyclic secondary amine, preferably pyrrolidine, ina water-immiscible solvent forming with same an azeotropic mixture,preferably toluene. Compounds of the formula (XVIII) are novel.

The invention also relates to the synthesis of the compounds of theformula (I) starting from 4-chromanone of the formula (XVIII), byconverting same into chromene of the formula (V) through 4-chromanone ofthe formula (XIX). The chromene of the formula (V) is converted into a3-bromo-4-chromanol of the formula (VII), from which a compound of theformula (I) is prepared through a 3,4-epoxy derivative of the formula(VIII) without isolating same (reaction scheme 4). ##STR12##

The potassium canal activating type compounds of the formula (I) showhypotensive activity, and can be used in the treatment of hypertension.Accordingly, the present invention also relates to pharmaceuticalcompositions containing as active ingredient a compound of the formula(I) in an effective amount together with pharmaceutically acceptablecarriers, as well as to the preparation of said pharmaceuticalcompositions.

The pharmaceutical compositions according to the invention are preparedby using usual formulating auxiliaries. The formulation is carried outby methods generally used in the preparation of the known hypotensiveagents.

Chemical examples

The process according to the invention is illustrated by the followingnon-limiting examples.

EXAMPLE 1 Preparation of (+/-)-6,7-dimethoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol

2.20 g (10 mmoles) of 6,7-dimethoxy-2,2-dimethyl-2H-chromene preparedaccording to T. Timar and J. Cs. Jaszberenyi in J. Her. Chem. 25, 871(1988)! are dissolved in 20 ml of dimethyl sulfoxide. The dimethylsulfoxide contains 0.40 ml of water as well. Then 1.78 g (10 mmoles) ofN-bromo-succinimide are added in small portions under vigorous stirringand cooling with ice. The reaction mixture is stirred at roomtemperature for 1 hour and poured onto 200 g of ice. The precipitatedwhite crystalline substance is filtered off, washed with water anddried. It is pulped with hexane to obtain 2.93 g of6,7-dimethoxy-trans-3-bromo-3,4-dihydro-2,2-dimethyl-2H-benzo (b)pyran-4-ol.

M.p.: 134°-135° C.

NMR (CDCl₃): 1.41 (3H, 1.57 (3H), 2.47 (1H, changeable), 4.12 (1H, d,J=10), 4.86 (1H, m), 6.35 (1H), 6,93 (1H).

2.85 g (9 mmoles) of bromohydrine derivative thus obtained are dissolvedin 15 ml of 2-pyrrolidone and 2.01 g (18 mmoles) of potassiumtert-butoxide are added thereto portionwise under vigorous stirring andcooling. The reaction mixture is stirred for another 2 hours at roomtemperature, 100 ml of water are added thereto and the product obtainedis extracted with chloroform. The organic phase is washed neutral withwater and dried on sodium sulfate to obtain the title product in a yieldof 2.08 g.

M.p.: 171°-172° C.

NMR (CDCl₃): 1.25 (3H), 1.48 (3H), 2.07 (2H, m), 2.57 (2H, m), 3.22 (3H,1 changeable H, broad m), 3.72 (1H, d, J=10), 3.77 (3H), 3.83 (3H), 5.22(1H, d, J=10), 6.38 (1H), 6.40 (1H).

EXAMPLE 2 Preparation of(+/-)-6-methoxy-7-ethoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol

The process as described in Example 1 is followed.

M.p.: 157°-158° C.

NMR (CDCl₃): 1.26 (3H), 1.45 (3H, t, J=6), 1.49 (3H), 2.07 (2H, m), 2.58(2H, m), 3.20 (3H, 1 changeable H, broad m), 3.72 (1H, d, J=10), 3.78(3H), 4.03 (2H, m), 5.21 (1H, d, J=10), 6.38 (2H).

EXAMPLE 3 Preparation of(+/-)-6-ethoxy-7-methoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b) pyran-3-ol

The process as described in Example i is followed.

M.p.: 164°-165° C.

NMR (CDCl₃): 1.27 (3H), 1.42 (3H, t, J=6), 1.50 (3H), 2.08 (2H, m), 2.58(2H, m), 3.21 (3H, 1 changeable H, m), 3.74 (1H, d, J=10), 3.83 (3H),3.97 (2H, m), 5.21 (1H, d, J=10), 6.40 (1H), 6.42 (1H).

EXAMPLE 4 Preparation of(+/-)-6-methoxy-7-benzyloxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b) pyran-3-ol

The process as described in Example 1 is followed.

M.p.: 211°-212.5° C.

NMR (CDCl₃): 1.25 (3H), 1.47 (3H), 2.07 (2H, m), 2.57 (2H, m), 3.18 (3H,1 changeable H, m), 3.72 (1H, m), 3.80 (3H), 5.07 (2H), 5.21 (1H, d,J=10), 6.42 (2H), 7.38 (5H, m).

EXAMPLE 5 Preparation of(+/-)-6-methoxy-7-hydroxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b) pyran-3-ol

0.39 g (1 mmole) of the 6-methoxy-7-benzyloxy derivative prepared asdescribed in Example 4 are dissolved in 20 ml of methanol. 0.1 g of 10%palladium on charcoal catalyst is added thereto and the reaction mixtureis hydrogenated at a hydrogen pressure of 5.0 bar under stirring. Thereaction time is 6 hours. The catalyst is filtered off and the solutionis evaporated. The oily product is dissolved in 50 ml of chloroform andwashed with water. The phases are separated, dried over sodium sulfateand evaporated to obtain the title product in a yield of 0.25 g.

M.p.: 260° C. (decomposition).

NMR (CDCl₃): 1.25 (3H), 1.47 (3H), 2.07 (2H, m), 2.58 (2H, m), 3.23 (3H,1 changeable H, m), 3.74 (1H, m), 3.81 (3H), 5.21 (1H, d, J=10), 5.65(1H, changeable), 6.36 (1H), 6.43 (1H).

EXAMPLE 6 Preparation of(+/-)-6,7-dibenzyloxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b) pyran-3-ol

The process as described in Example i is followed.

M.p.: 162°-163° C.

NMR (CDCl₃): 1.23 (3H), 1.46 (3H), 1.67 (1H, m), 1.91 (1H), m), 2.42(2H, m), 2.71 (1H, m), 3.02 (2H, m), 3.63 (1H, m), 5.12 (5H, m), 6.32(1H), 6.46 (1H), 7.35 (10H).

EXAMPLE 7 Preparation of(+/-)-6,7-dihydroxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol

A 6,7-dibenzyloxy derivative prepared as described in Example 6 ishydrogenated as described in Example 5. The reaction time is 10 hours.

M.p.: decomposition.

NMR (CDCl₃): 1.26 (3H), 1.48 (3H), 2.07 (2H, m), 2.57 (2H, m), 3.23 (3H,1 changeable H, m), 3.75 (1H, m), 5.22 (1H, d, J=10), 5.70 (2H, broad,changeable), 6.33 (1H), 6.46 (1H).

EXAMPLE 8 Preparation of(+/-)-6,7-methylenedioxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b) pyran-3-ol

The process as described in Example i is followed.

M.p.: 161°-162° C.

NMR (CDCl₃): 1.25 (3H), 1.48 (3H), 2.08 (2H, m), 2.60 (2H, m), 3.22 (3H,1 changeable H, m), 3.72 (1H, d, J=10), 5.15 (1H, d, J=10), 5.90 (2H,m), 6.35 (2H).

EXAMPLE 9 Preparation of (+/-)16-bromo-7-methoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo (b) pyran-3-ol

1.9 g (10 mmoles) of 7-methoxy-2,2-dimethyl-2H-chromene are dissolved in20 ml of dimethyl-sulfoxide containing 0.40 ml of water, too. 3.56 g (20mmoles) of N-bromo-succinimide are added thereto portionwise undervigorous stirring and external cooling with icy water. The reactionmixture is stirred at room temperature then poured onto 200 g of crushedice. The precipitated white crystalline substance is filtered off,washed with water and dried. The product is pulped with hexane to obtain3.09 g of6-bromo-7-methoxy-trans-3-bromo-3,4-dihydro-2,2-dimethyl-2H-benzo (b)pyran-4-ol.

M.p.: 58°-59° C.

NMR (CDCl₃): 1.42 (3H), 1.61 (3H), 2.70 (1H, changeable), 3.68 (3H),4.08 (1H, d, J=10), 4.85 (1H, d, J=10), 6.35 (1H), 7.62 (1H).

2.92 g (8 mmoles) of the bromohydrine derivative thus obtained aredissolved in 20 ml of 2-pyrrolidone, then 1.78 g (16 mmoles) ofpotassium tert-butoxide are added thereto under vigorous stirring andexternal cooling with icy water. The reaction mixture is stirred at roomtemperature for 4 hours, 100 ml of water are added thereto and theproduct is extracted with chloroform. The phase containing thechloroform is washed neutral with water, dried over sodium sulfate andevaporated to obtain the title product in a yield of 2.39 g.

M.p.: 165°-166° C.

NMR (CDCl₃): 1.27 (3H), 1.52 (3H), 2.13 (2H, m), 2.70 (2H, m), 3.25 (3H,1 changeable H, m), 3.76 (1H, d, J=10), 3.86 (3H), 5.22 (1H, d, J=10),6.41 (1H), 7.05 (1H).

EXAMPLE 10 Preparation of(+/-)-6-chloro-7-methoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b) pyran-3-ol

Starting from 6-chloro-7-methoxy-2,2-dimethyl -2H-chromene preparedaccording to P. Sebok et al in Acta Chim. Hung 126 (4), 471 (1989)! oneproceeds as described in Example 1.

M.p.: 196°-197.5° C.

NMR (CDCl₃): 1.27 (3H), 1.51 (3H), 2.10 (2H, m), 2.58 (2H, m), 3.16 (3H,1 changeable H, m), 3.72 (1H, m), 3.85 (3H), 5.21 (1H, d, J=10), 6.42(1H), 6.88 (1H).

EXAMPLE 11 Preparation of(+/-)-6-nitro-7-methoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl-2H-benzo(b)pyran-3-ol

2.06 g (10 mmoles) of 7-methoxy-2,2-dimethyl-4-chromanone are dissolvedin 12.5 ml of acetic anhydride. 3.02 g (12.5 mmoles) of Cu(NO₃)₂ *3H₂ Oare added thereto in small portions under vigorous stirring while thetemperature rises to 70° C. Then the mixture is stirred at 40° C. for1.5 hours and poured onto 200 g of crushed ice. 1.88 g of yellowishcrystalline 6-nitro-7-methoxy-2,2-dimethyl-4-chromanone are obtained,which is recrystallized in ethanol.

M.p.: 259°-261° C.

NMR (CDCl₃): 1.50 (6H), 2.72 (2H), 3.97 (3H), 6.52 (1H), 8.51 (1H).

1.75 g (7 mmoles) of 6-nitro-7-methoxy-2,2-dimethyl-4-chromanone aredissolved in 30 ml of methanol. 0.53 g (14 mmoles) of sodium boronhydride are added under vigorous stirring, the mixture is stirred atroom temperature for 1 hour, the methanol is distilled off in vacuo, 100ml of dichloromethane are added thereto and it is washed neutral withwater. The organic phase is dried on sodium sulfate, dried andevaporated. 50 ml of benzene and 0.1 g of paratoluol sulfonic acid areadded and boiled under reflux for 1 hour. The cooled solution is washedwith water, dried over sodium sulfate and the benzene is distilled offin vacuo to obtain 1.48 g of 6-nitro-7-methoxy-2,2-dimethyl-2H-chromane.

M.p.: 79°-80° C.

NMR (CDCl₃): 1.46 (6H), 3.92 (3H), 5.60 (1H, d, J=10), 6.27 (1H, d,J=10), 6.43 (1H), 7.70 (1H).

1.41 g (6 mmoles) of 6-nitro-7-methoxy-2,2-dimethyl-2H-chromene aredissolved in 15 ml of dimethyl sulfoxide containing 0.3 ml of water.1.06 g (6 mmoles) of N-bromosuccinimide are added under vigorousstirring and external cooling with ice. The reaction mixture is stirredat room temperature for 1.5 hours and poured onto 200 g of crushed ice.The precipitated white crystalline substance is filtered off, washedwith water and dried to obtain 1.85 g of6-nitro-7-methoxy-trans-3-bromo-3,4-dihydro-2,2-dimethyl-2H-benzo(b)pyran-4-ol.

M.p.: 143°-145° C.

NMR (CDCl₃): 1.45 (3H), 1.63 (3H), 2.72 (1H, broad, changeable), 3.90(3H), 4.08 (1H, d, J=9.5), 4.87 (1H, d, J=9.5), 6.44 (1H), 8.19 (1H).

1.82 g (5.5 mmoles) of the bromohydride derivative thus obtained aredissolved in 15 ml of 2-pyrrolidone, then 1.23 g (11 mmoles) of 1.23 gof potassium tert-butoxide are added portionwise under vigorous stirringand external cooling with icy water. The reaction mixture is stirred atroom temperature for 2 hours, 100 ml of water are added and the productis extracted with chloroform. The organic phase is washed neutral withwater, washed, dried over sodium hydride and evaporated to obtain thetitle product in a yield of 1.50 g.

M.p.: 255°-257° C.

NMR (CDCl₃): 1.20 (3H), 1.44 (3H), 1.93 (2H, m), 2.37 (2H, m), 2.92 (2H,m), 3.67 (1H, dd, J₁)=10, J₂ =6), 3.83 (3H), 4.90 (1H, d, J₁ =10), 5.73(1H, d, J₂ =6, changeable), 6.69 (1H), 7.43 (1H).

EXAMPLE 12 Preparation of(+/-)-6-nitro-7-ethoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol

The process as described in Example 11 is followed.

M.p.: 225.5°-226.5° C.

NMR (CDCl₃): 1.31 (3H), 1.47 (3H, t, J=6), 1.53 (3H), 2.12 (2H, m), 2.70(2H, m), 3.10. (1H, m), 3.33 (1H, m), 3.73 (1H, m), 3.93 (1H, m,changeable), 4.11 (2H, m), 5.22 (1H, d, J=10), 6.45 (1H), 7.58 (1H).

EXAMPLE 13 Preparation of(+/-)-6-nitro-7-n-propoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol

The process as described in Example 11 followed.

M.p.: 207.5°-209.5° C.

NMR (CDCl₃): 1.07 (3H, t, J=6), 1.30 (3H), 1.53 (3H), 1.86 (2H, m), 2,11(2H, m), 2.57 (2H, m), 3.22 (3H, 1 changeable H, m), 3.74 (1H, m), 4.00(2H, m), 5,25 (1H, d, J=10), 6.45 (1H), 7.59 (1H).

EXAMPLE 14 Preparation of(+/-)-6-nitro-7-isopropoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b) pyran-3-ol

The process as described in Example 11 is followed.

M.p.: 221.5°-222.5° C.

NMR (CDCl₃): 1.31 (3H), 1.38 (6H), 1.52 (3H), 2.07 (2H, m), 2.56 (2H,m), 3.12 (1H, m), 3.35 (1H, m), 3.72 (1H, dd, J₁ =6, J₂ =10), 4.09 (1H,d, changeable, J₁ =6), 1H, m), 5.21 (1H, d, J₂ =10), 6.45 (1H), 7.53(1H).

EXAMPLE 15 Preparation of (+/-)-6-cyano-7-methoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo (b) pyran-3-ol

4.50 g (17.8 mmoles) of6-formyl-4-chloro-7-methoxy-2,2-dimethyl-2H-chromene prepared accordingto the method of P. Brown et al, J. Chem. Soc. Perkin Trans. (I), 1127(1985) and T. Eszenyi and T. Timar, Synth. Comm., 20 (1990) 3219! aresuspended in 40 ml of 100% of formic acid, 1.50 g (21 mmoles) ofhydroxyl ammonium chloride and 2.50 g (24 mmoles) of sodium carbonate oran equivalent amount of sodium formiate are added. The reaction mixtureis boiled under reflux for 3 hours, then poured onto 200 g of crushedice. The separated beige precipitate is filtered off, washed with waterand dried to obtain the below mentioned product in a yield of 3.89 g.

M.p.: 116°-118° C.

NMR (CDCl₃): 1.50 (6H), 2.72 (2H), 3.95 (3H), 6.45 (1H), 8.15 (1H).

4.0 g (17.3 Moles) of 6-cyano-7-methoxy-2,2-dimethyl-4-chromanone and0.72 g (19 mmoles) of sodium boron hydride are suspended in 40 ml ofbenzene, then 10 ml of methanol are added dropwise while heated toreflux temperature. After a reaction time of half an hour the reactionmixture is cooled to 5°-10° C., the precipitate is filtered off and thebenzene solution is evaporated. The evaporation residue is againdissolved in 20 ml of benzene, 0.4 g of para-toluene sulfonic acid areweighed in and the reaction mixture is boiled under reflux. Then it iscooled down, washed with water, dried on sodium sulfate and evaporatedto obtain 3.12 g of a white crystalline substance.

M.p.: 92°-94° C.

NMR (CDCl₃): 1.45 (6H), 3.90 (3H), 5.57 (1H, d, J=10), 6.25 (1H, d,J=10), 6.40 (1H), 7.15 (1H).

2.15 g (10 mmoles) of 6-cyano-7-methoxy-2,2-dimethyl-2H-chromene aredissolved in 20 ml of dimethyl sulfoxide containing also 0.4 ml ofwater. Then 1.78 g (10 mmoles) of N-bromo-succinimide are added underexternal cooling with water and the reaction mixture is allowed to reactfor 2 hours at room temperature. Then it is poured onto 200 g of ice,the separated white precipitate is filtered, washed with water and driedto obtain 2.55 g of6-cyano-7-methoxy-3,4-dihydro-2,2-dimethyl-trans-3-bromo-4-hydroxy-2H-benzo-(b)pyran.

M.p.: 144°-146° C.

NMR (CDCl₃) :1.45 (3H), 1.65 (3H), 2.85 (1H, changeable), 3.88 (3H),4.08 (1H, d, J=10), 4.88 (1H, d, J=10), 6.38 (1H), 7.73 (1H).

2.55 g (8.2 mmoles) of the bromohydrine derivative thus-obtained aredissolved in 8 ml of 2-pyrrolidone, then 1.99 g (17.2 mmoles) of 97%potassium tert-butoxide are added under external cooling with water. Thereaction mixture is stirred for 4 hours at room temperature, poured onto100 g of crushed ice, the white precipitate is filtered off, washed withicy water, dried and crystallized from butanol to obtain the titleproduct in an amount of 1.81 g.

M.p.: 239°-241° C.

NMR (CDCl₃): 1.30 (3H), 1.55 (3H), 2.13 (2H, m), 2.58 (2H, t), 3.09-3.35(2H, m), 3.73 (1H, d, J=10), 3.88 (3H), 5.20 (1H, d, J=10), 6.40 (1H),7.13 (1H).

EXAMPLE 16 Preparation of(+/-)-6-cyano-7-ethoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b) pyran-3-ol

The process as described in Example 15 is followed.

M.p.: 227°-229° C.

NMR (CDCl₃): 1.30 (3H), 1.48 (3H, t), 1.53 (3H), 2.13 (2H, m), 2.63 (2H,t), 3.08 (1H, m), 3.40 (1H, m), 3.73 (1H, d, J=10), 4.10 (2H, m), 5.18(1H, d, J=10), 6.38 (1H), 7.10 (1H).

EXAMPLE 17 Preparation of(+/-)-6-cyano-7-propoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b) pyran-3-ol

The process as described in Example 15 is followed.

M.p.: 211°-213° C.

NMR (CDCl₃): 1.05 (3H, t), 1.30 (3H), 1.55 (3H), 1.85 (2H, m), 2.13 (2H,m), 2.58 (2H, t), 3.0 (1H, m), 3.35 (1H, m), 3.70 (1H, d, J=10), 3.95(2H), m), 5.20 (1H, d, J=10), 6.38 (1H), 7.10 (1H).

EXAMPLE 18 Preparation of(+/-)-6-cyano-7-(1-methylethoxy)-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)-pyran-3-ol

The process as described in Example 15 is followed.

M.p.: 213°-215° C.

NMR (CDCl₃): 1.30 (3H), 1.40 (6H, t), 1.55 (3H), 2.13 (2H, m), 2.58 (2H,t), 3.10 (1H, m), 3.35 (1H, m), 3.70 (1H, d, J=10), 4.55 (1H, m), 5.20(1H, d, J=10), 6.38 (1H), 6.38 (1H), 7.10 (1H).

EXAMPLE 19 Preparation of (+/-)-6-cyano-7-(1-methylpropoxy)-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl) -2H-benzo-(b)pyran-3-ol

The process as described in Example 15 is followed.

M.p.: 199°-210° C.

NMR (CDCl₃): 1.02 (3H, t), 1.32 (6H, m), 1.55 (3H), 1.72 (2H, m), 2.12(2H, m), 2.57 (2H, t), 3.10 (1H, m), 3.32 (1H, m), 3.72 (2H, m), 4.30(1H, m), 5.17 (1H, d, J=10), 6.35 (1H), 7.10 (1H).

EXAMPLE 20 Preparation of (+/-)-7-benzyloxy-6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo (b) pyran-3-ol

The process as described in Example 15 is followed.

M.p.: 233°-235° C.

NMR (CDCl₃): 1.28 (3H, s), 1.52 (3H, s), 2.12 (2H, m), 2.57 (2H, t),3.07 (1H, m), 3.30 (2H, m), 3.70 (1H, m), 5.17 (3H, m), 6.45 (1H, s),7.15 (1H, s).

EXAMPLE 21 Preparation of(+/-)-7-hydroxy-6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b) pyran-3-ol

Starting from a 6-cyano-7-benzyloxy derivative prepared according toExample 20, the process as described in Example 5 is followed.

M.p.: 280° C. (decomposition).

NMR (DMSO-d₆): 1.16 (3H, s), 1.40 (3H, s), 1.97 (2H, m), 2.38 (2H, m),2.92 (1H, m), 3.30 (1H, m), 3.62 (1H, d, J=10), 4.85 (1H,d, J=10), 5.64(1H, changeable H), 6.37 (1H, s), 7.06 (1H, s), 11.00 (1H, changeableH).

EXAMPLE 22 Preparation of(+/-)-7-allyloxy-6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b) pyran-3-ol

0.30 g (1 mmole) of a compound according to Example 21 is reacted with0.34 g (1.2 mmoles) of allylbromide in 15 ml of acetone for 4.5 hours atreflux temperature in the presence of 0.20 g of potassium carbonate anda catalytic amount of potassium iodie. The reaction mixture is cooledback, filtered off and evaporated and the rough product obtained isrecrystallized from ethyl acetate.

M.p.: 204°-206° C.

NMR (CDCl₃): 1.28 (3H, s), 1.52 (3H, s), 2.10 (2H, m), 2.54 (2H, t),3.05 (1H, m), 3.32 (1H, m), 3.72 (2H, m, 1 changeable H), 4.59 (2H, d,J=6), 5.18 (1H, d, J=10), 5.25-5.55 (2H, m), 5.90-6.15 (1H, m), 6.39(1H, s), 7.12 (1H, s).

EXAMPLE 23 Preparation of(+/-)-6-formyl-7-methoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol

Starting from 6-formyl-7-methoxy-2,2-dimethyl -2H-chromene preparedaccording to the method of S. Yamaguchi et al in Bull. Chem. Sc. japan,57, 442 (1984)! one proceeds as described in Example 15.

(+/-)-trans-3-bromo-3,4-dihydro-2,2-dimethyl-6-formyl-7-methoxy-2H-benzo (b) pyran-4-ol

M.p.: 149°-151° C.

NMR (CDCl₃): 1.45 (3H, s), 1.65 (3H, s), 2.93 (1H, broad), 3.88 (3H, s),4.10 (1H, d, J=10), 4.90 (1H, d, J=10U, 6.38 (1H, s), 8.03 (1H, s),10.28 (1H, s).

(+/-)-6-Formyl-7-methoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol

M.p.: 219°-221° C.

NMR (CDCl₃): 1.30 (3H, s), 1.55 (3H, s), 2.10 (2H, m), 2.55 (2H, m),3.00-3.40 (2H, m), 3.60 (3.90 (5H, m), 5.22 (1H, d, J=10), 6.40 (1H, s),7.45 (1H, s), 10.25 (1H, s).

EXAMPLE 24 Preparation of(+/-)-7-ethoxy-6-formyl-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol

The process as described in Example 21 is followed.

M.p.: 203°-206° C.

NMR (CDCl₃): 1.30 (3H, s), 1.45 (3H, t), 1.55 (3H, s), 2.10 (2H, m),2.55 (2H, m), 3.00-3.40 (2H, m), 3.60-3.80 (2H, m), 4.08 (2H, q), 5.22(1H, d, J=10), 6.38 (1H, s), 7.45 (1H, s), 10.30 (1H, s).

EXAMPLE 25 Preparation of(+/-)-6-formyl-7-propoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b) pyran-3-ol

The process as described in Example 21 is followed.

M.p.: 190°-192° C.

NMR (CDCl₃): 1.05 (3H, t), 1.30 (3H, s), 1.55 (3H, s), 1.85 (2H, m),2.10 (2H, m), 2.55 (2H, m), 3.00-3.40 (2H, m), 3.60-3.80 (2H, m), 3.95(2H, q), 5.22 (1H, d, J=10), 6.38 (1H, s), 7.45 (1H, s), 10.32 (1H, s).

EXAMPLE 26 Preparation of (+/-)-(3,4-dihydro-2,2-dimethyl-7-methoxy-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo (b)pyran-3-ol-6-yl)-propane carbonitrile

5.00 g (19.8 mmoles) of 6-formyl-4-chloro-7-methoxy-2,2-dimethyl-2H-chromane are dissolved at room temperature in100 ml of acetonitrile. Then 2.70 g (23.3 mmoles) of 97% potassiumtert-butoxide are added and the reaction mixture is boiled under refluxfor 1 hour. The reaction mixture is then evaporated and poured onto 200g of crushed ice, extracted three time with 50 ml of chloroform each,the chloroformic solution is dried and evaporated to obtain2-(2,2-dimethyl-4-chloro-7-methoxy-2H-chromene-6-yl)-trans-propenecarbonitrile in the form of a yellow oil.

NMR (CDCl₃): 1.48 (6H, s), 3.85 (3H, s), 5.70 (1H, s), 5.95 (1H, d,J=17), 6.40 (1H, s), 7.42 (1H, :s), 7.55 (1H, d, J=17) .

The 2-(2,2-dimethyl-4-chloro-7-methoxy-2H-chromene-6-yl)-trans-propenecarbonitrile is dissolved in 25 ml of acetonitrile and 10 ml of 70%perchloric acid are added thereto. The reaction mixture is let to reactat 40° C. for an hour. It is then cooled with ice, poured onto 200 g ofcrushed ice, extracted with chloroform, dried on sodium sulfate andevaporated. The evaporation residue is dissolved in 15 ml of methanoland cooled down to obtain 0.97 g of white crystallinetrans-2-(2,2-dimethyl-7-methoxy -4-chromanone-6-yl)-propenecarbonitrile.

M.p.: 127°-129° C.

NMR (CDCl₃): 1.48 (6H, s), 2.71 (2H, s), 3.93 (3H, s), 6.00 (1H, d,J=17), 6.42 (1H, s), 7.52 (1H, d, J=17), 7.95 (1H, s).

0.95 g (3.45 mmoles) oftrans-2,2-dimethyl-7-methoxy-4-chromanone-6-yl)-propene carbonitrile aredissolved in 30 ml of acetone, 0.10 g of 10% palladium on charcoalcatalyst are added thereto and the reaction mixture is reduced at apressure of 5.0 bar for 4 hours. Then the catalyst is filtered off andthe solution is evaporated to obtain white crystalline6-β-cyanoethyl-7-methoxy-2,2-dimethyl-4-chromanone in a yield of 97%.

M.p.: 105°-107° C.

NMR (CDCl₃): 1.45 (6H, s), 2.60 (2H, t), 2.68 (2H, s), 2.90 (2H, s),3.87 (3H, s), 6.38 (1H, s), 7.65 (1H, s).

Further one proceeds as described in Example 15 to obtain whitecrystalline (+/-)-(3,4-dihydro-2,2-dimethyl-7-methoxy-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo (b)pyran-3-ol-6-yl)-propane carbonitrile.

M.p.: 180°-182° C.

NMR (CDCl₃): 1.18 (3H, s), 1.50 (3H, s), 2.08 (2H, m), 2.58 (4H, m),2.65 (1H, m), 2.95 (1H, m), 3.23 (2H, m), 3.50 (1H, m), 3.70 (1H, m),3.78 (3H, s), 5.20 (1H, d, J=10), 6.25 (1H, s), 6.25 (1H, s), 6.73 (1H,s).

EXAMPLE 27 Preparation of (+/-)-(3,4-dihydro-2,2-dimethyl-7-ethoxy-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo (b)pyran-3-ol-6-yl)-propane carbonitrile

The process as described in Example 25 is followed.

M.p.: 208°-210° C.

NMR (CDCl₃): 1.28 (3H, s), 1.40 (3H, t), 1.50 (3H, s), 2.08 (2H, m),2.60 (5H, m), 3.68 (1H, m), 2.95 (1H, m), 3.25 (2H, m), 3.73 (2H, m),4.00 (2H, q), 5.23 (1H, d, J=10), 6.35 (1H, s), 6.73 (1H, s).

EXAMPLE 28 Preparation of (+/-)-6-cyano-7-methoxy-3,4-dihydro-2,2-diethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo (b) pyran-3-ol

1.52 g (10.0 mmoles) of resacetophenone are dissolved in 1.20 g (14.0mmoles) of diethyl ketone, then 1.42 g (20.0 mmoles) pyrrolidineprepared according to the method of H. J. Kabbe in Synthesis, 886(1978)! are added thereto. The reaction mixture is allowed to stand atroom temperature for 24 hours, then 40 ml of toluene are added. Thereaction mixture is boiled under reflux for 10 hours by using a waterseparator. Then it is cooled back, washed subsequently with 10%hydrochloric acid and water, thereafter it is dried and evaporated toobtain 1.41 g of 2,2-diethyl-7-hydroxy-4-chromanone in the form of apale yellow viscous oil which crystallizes on standing.

M.p.: 97°-99° C.

NMR (CDCl₃): 0.92 (6H, t), 1.75 (4H, m), 2.68 (2H, s), 6.38 (1H, d,J=2), 6.50 (1H, dd, J₁ =2, J₂ =8.5), 7.78 (1H, d, J₂ =8.5 ).

1.41 g (6.40 mmoles ) of 2,2-diethyl-7-hydroxy-4-chromanone thusobtained is methylated with methyl iodide according to the method of T.Timir et al Acta Chimica Hungarica, 125(2), 303 (1980)! to obtain 1.36 gof 2,2-diethyl-7-methoxy-4-chromanone in the form of a pale yellow oil.

NMR (CDCl₃): 0.95 (6H, t), 1.75 (4H, m), 2.75 (2H, s), 3.80 (3H, s),6.40 (1H, d, J₁ =2), 6.55 (1H, dd, J₁ =2, J₂ =8.5), 7.75 (1H, d, J₂=8.5).

Furtheron one proceeds as described in Example 15 to obtain6-cyano-7-methoxy-3,4-dihydro-2,2-diethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol in the form of awhite crystalline substance.

M.p.: 193°-195° C.

NMR (CDCl₃): 0.90 (3H, t), 1.05 (3H, t), 1.60-2.20 (6H, multiplet), 2.55(2H, m), 3.05 (1H, m), 3.30-3.60 (2H, multiplet), 3.70 (1H, d, J=10),3.85 (3H, s), 3.90 (1H, m, changeable), 5.30 (1H, d, J=10), 6.42 (1H,s), 7.10 (1H, s).

EXAMPLE 29 Preparation of(+/-)-6-cyano-7-ethoxy-3,4-dihydro-2,2-diethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b) pyran-3-ol

The process as described in Example 28 is followed.

M.p.: 187°-189° C.

NMR (CDCl₃): 0.90 (3H, t), 1.05 (3H, t), 1.45 (3H, t), 1.70-2.10 (6H,multiplet), 2.55 (2H, m), 3.05 (1H, m), 3.40 (1H, m), 3.95-4.10 (4H,multiplet), 5.30 (1H, d, J=10), 6.40 (1H, s), 7.10 (1H, s).

BIOLOGICAL EXAMPLES

1. Measuring the bandage to potassium canal and selectivity on isolatedarteria mesenterica anterior of rabbits

The measurements were carried out by adapting the methods of R. P. Hofet al (Circulation Research, 1988, 62, 679) and J. C. Clapham et al (J.Auton. Pharmac. , 1987, 7, 233).

Rabbits of both sexes weighing 2000-2500 g were anesthetized by a hit atthe nape, the abdominal wall was cut open and the arteria mesentericaanterior was mounted after exsanguination. The artery was put into aKrebs solution of a temperature of 37° C. infiltrated with carbogenewhile removing the interstitial residues. Then a 2 mm wide spiral is cutfrom the artery and this artery stripe is prestretched in an organ potin Krebs solution of a temperature of 37° C., infiltrated withcarbogene, by a stretching of 0.5 g.

In the experiment Hugo Basile type dynamometer heads, Hugo Basile typeamplifiers and Perkin Elmer type potentiometer have been used foramplifying and fixing the signs.

Two parallel organs were used for the qualitative tests. One of them wascontracted by adding 30 mmoles of KCl after an incubation time of 1hour, the other one by 5 μmoles of adrenaline. Then the arteries wererelaxed by the cumulative addition of the substance to be examined. Thesystem was washed with a Krebs solution containing 30 mmoles oftetraethyl ammonium bromide (TEA) and the organs were incubated for 30minutes in a TEA-containing medium. After incubation the organs wereagain contracted with potassium and noradrenaline and a dilatation wasinduced by using the substance to be examined. In a quantitative testorgans contracted with 5 μmoles of noradrenaline were relaxed with thesubstance to be examined and the dose inducing a 50% dilatation wasdetermined.

    ______________________________________                                        Compound                                                                              pA.sub.2   Selectivity                                                                             Mechanism of effect                              ______________________________________                                        BRL 34915                                                                             6.64 ± 0.23                                                                           selective Potassium canal activator                        Example 1                                                                             5.78 ± 0.24                                                                           selective Potassium canal activator                        Example 9                                                                             6.08 ± 0.32                                                                           selective Potassium canal activator                        Example 10                                                                            5.47 ± 0.60                                                                           selective Potassium canal activator                        Example 11                                                                            5.65 ± 0.27                                                                           selective Potassium canal activator                        Example 15                                                                            6.76 ± 0.23                                                                           selective Potassium canal activator                        ______________________________________                                    

The compounds according, to the other Examples have also been examinedand found to be effective.

It has been recognized that the compounds of the formula (I) can be usedfor treating different types of hypertension such as essentialhypertension or secondary hypertension (of renal or hormonal origin) orany other disease requiring the decrease of the blood pressure by anantihypertensive composition.

2. Decrease of blood pressure on normotensive rats measured by averagearterial tension

Wistar rats of both sexes weighing 230-260 g were used in theexperiments. The rats were narcotised by 40 mg/kg of pentobarbital. Thetrachea was mounted and a polyethylene canula was introduced into thetrachea, vena jugularis sinester and to the arteria carotis communissinester. The substances to be examined were introduced into theorganism of the animal through the duodenum. The pulsatory, systolic anddiastolic blood pressure and the pulse were continuously measured byusing a Statham type tensiometer head and haemodynamic measuring systemproduced by the Hungarian firm Experimetria Kft. After the bloodpressure has become stable 0.75 μg of adrenaline were administeredintravenously to measure the effect of alpha-adrenergic receptors on theblood pressure. After the hypertension has ceased 0.1 μg/kg ofisoproterenole is added in order to characterize the activity of theβ-adrenerg receptors. After tachycardia has ceased the test compound wasadministered i.d. and the treatment with the receptor stimulants wasrepeated after an hour in order to characterize the effect of the testcompound on adrenergic receptor subclasses.

Change of the blood pressure on normotensive rats measured on six testanimals

    ______________________________________                                                           Average                                                              Time     arterial                                                   Compound  (min)    tension  Decrease Pulse                                    ______________________________________                                        BRL 34915 0        112 ± 9                                                                             --       368 ± 44                                        1        45 ± 2                                                                              -67      368 ± 31                              in a dose 10       45 ± 2                                                                              -67      382 ± 25                              of 1 mg/kg                                                                              30       49 ± 4                                                                              -63      377 ± 19                                        60       61 ± 11                                                                             -51      373 ± 12                              Example 1 0        107 ± 11                                                                            --       394 ± 27                                        1        56 ± 6                                                                              -51      403 ± 34                              in a dose 10       56 ± 6                                                                              -51      400 ± 31                              of 1 mg/kg                                                                              30       49 ± 4                                                                              -45      400 ± 31                                        60       71 ± 20                                                                             -36      382 ± 31                              Example 9 0        117 ± 19                                                                            --       406 ± 51                                        1        119 ± 16                                                                            +2       406 ± 51                              in a dose 10       58 ± 5                                                                              -59      436 ± 62                              of 10 mg/kg                                                                             30       65 ± 15                                                                             -52      430 ± 63                                        60       87 ± 18                                                                             -30      430 ± 63                              Example 10                                                                              0        108 ± 15                                                                            --       402 ± 4                                         1        62 ± 3                                                                              -46      418 ± 18                              in a dose 10       68 ± 6                                                                              -40      436 ± 18                              of 5 mg/kg                                                                              30       96 ± 15                                                                             -12      424 ± 10                                        60       109 ± 26                                                                            +1       396 ± 13                              Example 11                                                                              0        121 ± 21                                                                            --       388 ± 10                                        1        115 ± 11                                                                            -6       373 ± 15                              in a dose 10       97 ± 23                                                                             -24      394 ± 20                              of 1 mg/kg                                                                              30       105 ± 18                                                                            -16      382 ± 18                                        60       107 ± 12                                                                            -14      382 ± 18                              Example 15                                                                              0        125 ± 13                                                                            --       412 ± 45                                        1        92 ± 10                                                                             -33      439 ± 42                              in a dose 10       103 ± 5                                                                             -22      430 ± 45                              of 1 mg/kg                                                                              30       118 ± 15                                                                            -7       430 ± 45                                        60       122 ± 10                                                                            -3       412 ± 37                              ______________________________________                                    

What we claim is:
 1. A compound of the Formula (I) ##STR13## wherein R₁is C₁ to C₆ alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, aryloxy,aralkoxy, hydroxy, nitro, cyano, formyl, C₁ to C₆ acyl, cyano-C₁ -C₆alkyl or halo;R₂ is C₁ to C₆ alkoxy, alkenyloxy, alkynyloxy,cycloalkoxy, aryloxy, aralkoxy or hydroxy; or R₁ and R₂ together arealkylenedioxy; and R₃ and R₄ are each C₁ to C₆ alkyl.
 2. A compound ofthe Formula ##STR14## wherein R₁ is nitro, cyano or cyano-C₁ -C₆alkyl;R₂ is C₁ to C₄ alkoxy; and R₃ and R₄ are each C₁ to C₄ alkyl.
 3. Acompound of the Formula (I) defined in claim 1 and selected from thegroup consistingof:(+/-)-6,7-dimethoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol;(+/-)-6-bromo-7-methoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol;(+/-)-6-chloro-7-methoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol;(+/-)-6-nitro-7-methoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol; and(+/-)-6-cyano-7-methoxy-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol. 4.An anti-hypertensive pharmaceutical composition which comprises atherapeutically effective amount of a compound of the Formula (I)defined in claim 1 in combination with a pharmaceutically acceptableinert carrier.
 5. A method of treating hypertension in a mammaliansubject which comprises the step of administering to said mammaliansubject to be treated, a therapeutically effective amount of thecompound of the Formula (I) defined in claim
 1. 6. A process for thepreparation of a compound of the Formula (I) ##STR15## wherein R₁ is C₁to C₆ alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, aryloxy, aralkoxy,hydroxy, nitro, cyano, formyl, C₁ to C₆ acyl, cyano-C₁ -C₆ alkyl orhalo;R₂ is C₁ to C₆ alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy,aryloxy, aralkoxy or hydroxy; or R₁ and R₂ together are alkylenedioxy;and R₃ and R₄ are each C₁ to C₆ alkyl, which comprises the steps of:(a)reducing a compound of the Formula (XVIII) ##STR16## with a metalhydride to yield a compound of the Formula (XIX) ##STR17## (b)dehydrating the compound of the Formula (XIX) by boiling said compoundin a water immiscible solvent forming therewith an azeotropic mixture inthe presence of a catalytically effective amount of p-toluene sulfonicacid to obtain a compound of the Formula (V) ##STR18## (c) convertingthe compound of the Formula (V) with N-bromo-succinimide to a compoundof the Formula (VII) ##STR19## and (d) reacting the compound of theFormula (VII) with 2-pyrrolidone in the presence of an alkali metalalcoholate to obtain the compound of the Formula (I).
 7. The process forpreparing a compound of the Formula (I) defined in claim 6 wherein R₂ ishydroxy further comprising the step of catalytically hydrogenating underpressure a compound of the Formula (I) where R₂ is aralkoxy.
 8. Theprocess for preparing a compound of the Formula (I) defined in claim 6wherein R₂ is alkenyloxy or alkynyloxy further comprising the step ofreacting a compound of the Formula (I) where R₂ is hydroxy with analkenyl or alkynyl halogenide in the presence of an acid binding agentand a catalytic amount of potassium iodide.
 9. The process for preparinga compound of the Formula (I) defined in claim 6 wherein according tostep (a) the metal hydride is sodium borohydride.
 10. The process forpreparing a compound of the Formula (I) defined in claim 6 whereinaccording to step (d) the alkali metal alcoholate is potassiumtert-butoxide.
 11. The process for preparing a compound of the Formula(I) defined in claim 7 wherein R₂ is hydroxy in that the catalyst ispalladium-on-charcoal.
 12. The process for preparing a compound of theFormula (I) defined in claim 8 wherein R₂ is alkenyloxy or alkynyloxy inthat the acid binding agent is potassium carbonate.
 13. A process forpreparing a compound of the Formula (X) ##STR20## wherein R₂ is C₁ to C₄alkoxy; andR₃ and R₄ are each C₁ to C₄ alkyl, which comprises the stepof nitrating a compound of the Formula (IX) ##STR21## withcopper(II)nitrate in a carboxylic anhydride.
 14. A process for thepreparation of a compound of the Formula (XII) ##STR22## wherein R₂ isC₁ to C₄ alkoxy; andR₃ and R₄ are each C₁ to C₄ alkyl, which comprisesthe steps of(a) reacting a compound of the Formula (IX) ##STR23## in amixture of phosphorous trichloride oxide and dimethyl formamide toobtain a compound of the Formula (XI) ##STR24## (b) dissolving thecompound of the Formula (XI) in a carboxylic acid; and (c) boiling thedissolved compound of the Formula (XI) in the carboxylic acid in thepresence of hydroxylamine hydrochloride and an alkali metal formiate.15. A process for preparing a compound of the Formula (XV) ##STR25##wherein R₂ is C₁ to C₄ alkoxy; andR₃ and R₄ are each C₁ to C₄ alkyl,which comprises the step of:(a) condensing a compound of the Formula(XI) ##STR26## with acetonitrile in the presence of an alkali metalalcoholate to obtain a compound of the Formula (XIII) ##STR27## (b)reacting the compound of the Formula (XIII) with a mineral acid to yielda compound of the Formula (XIV) ##STR28## and; (c) hydrogenating thecompound of the Formula (XIV) in the presence of a catalyst underpressure.
 16. A process for preparing a compound of the Formula (XVIII)##STR29## wherein R₁ is hydrogen;R₂ is hydroxy; and R₃ and R₄ are eachC₂ to C₆ alkyl, which comprises reacting the compound of the Formula(XVI) ##STR30## with a compound of the Formula (XVII) ##STR31## in whichR₃ and R₄ are each C₂ to C₆ alkyl.
 17. The compound of the Formula (I)defined in claim 1 wherein R1 is cyano-C₁ to C₆ alkyl.